Physiology, Calcium


Article Author:
Elaine Yu


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Sandeep Sharma


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Updated:
3/9/2019 10:02:40 PM

Introduction

Calcium is an essential element that serves an important role in skeletal mineralization. More than 99% of the calcium in the body is stored in bone as hydroxyapatite. Calcium in this form provides skeletal strength as well as a reservoir for calcium to be released into the serum.

In serum, calcium exists in 3 forms: protein-bound, ionized (free), and complexed (chelated). Protein-bound calcium, which accounts for 40% of the serum calcium, cannot be used by tissues. Albumin and globulin are the primary calcium-binding proteins in the serum whereas calmodulin is the primary calcium-binding protein in the cell. Chelated calcium, which accounts for 9% of the serum calcium, allows calcium to be absorbed by various tissues or carried between parts of the body. Serum calcium is often chelated into the ionic complexes of calcium phosphate, calcium carbonate, and calcium oxalate. Finally, free calcium, which makes up 51% of the serum calcium, is utilized by the body to maintain physiologic functions. If the serum calcium concentration exceeds the 8.8 to 10.4 mg/dL, then the body is considered in a state of calcium toxicity.[1][2]

Organ Systems Involved

Calcium homeostasis is maintained by actions of hormones that regulate calcium transport in the gut, kidneys, and bone. The 3 primary hormones are parathyroid hormone (PTH) 1,25-dihydroxyvitamin D-3 (Vitamin D3), and calcitonin.

The parathyroid glands release parathyroid hormone (PTH) in response to a decrease in serum calcium. PTH acts on the kidneys to increase calcium reabsorption in the ascending loop of Henle, the distal convoluted tubule, and the collecting duct. The kidney also responds to PTH by increasing secretion of Vitamin D3, which in turn stimulates calcium absorption through the gut.  PTH acts on the bones to stimulate osteoclasts involved in bone reabsorption and the release of free calcium. All of these processes contribute to the rise in serum calcium.

Calcitonin is released by the thyroid parafollicular cells (C-cells) in response to an increase in serum calcium. Calcitonin acts on the bones to stimulate osteoblasts to deposit calcium in bones. Calcitonin also inhibits renal reabsorption of calcium, increasing urinary calcium excretion. Finally, calcitonin also inhibits calcium absorption in the intestines. These processes lead to a decrease in serum calcium.[3][4]

Function

Ionized calcium plays an important function in muscle contraction.  Skeletal muscle function is governed by an action potential that releases calcium stored in the sarcoplasmic reticulum. This calcium then binds to tropomyosin and allows for the interaction of myosin and actin in the sarcomere, leading to muscle contraction. In smooth muscle, second messenger systems trigger the release of calcium from the sarcoplasmic reticulum. Additionally, ligand-gated and voltage-gated calcium channels on the smooth muscle membrane allow for extracellular calcium to enter the cell. Calmodulin binds calcium ions and activates myosin light chain kinase to phosphorylase the myosin head, which then binds actin and causes smooth muscle contraction. Cardiac muscle is governed both by action potentials and extracellular calcium influx. The action potential triggers an inward flow of calcium that potentiates additional calcium release from the sarcoplasmic reticulum. The contraction of one cardiac muscle cell is communicated to adjacent cells through intercalated disks, thus allowing for the synchronized contraction of cardiac muscle. It is through this mechanism that calcium is used to stabilize the cardiac cell membrane against depolarization in severe hyperkalemia.

Ionized calcium also serves many microbiological functions, including activating protein kinases, enzyme phosphorylation, and mediating cell response to hormones such as epinephrine, glucagon, vasopressin (ADH), secretin, and cholecystokinin.[5][6][7]

Clinical Significance

It is important for the clinician to be aware of the causes of hypercelcemia and hypocalcemia because these diseases are potentially dangerous and either extreme may be life-threatening.

Hypercalcemia

Mild hypercalcemia (less than 11.5 mg/dL) is usually asymptomatic.  Elevations of calcium above 11.5 mg/dL can lead to nonspecific symptoms including nausea, vomiting, altered mental status, headache, confusion, abdominal or flank pain, constipation, depression, weakness, myalgias, arthralgias, polyuria, polydipsia, and nocturia. Severe cases of hypercalcemia can cause coma. Physical exam findings include hypertension, bradycardia, hyperreflexia, and tongue fasciculations.

The diagnosis of hypercalcemia is divided into PTH-mediated and non-PTH-mediated causes. PTH-mediated hypercalcemia is due to increased intestinal calcium absorption in response to elevated PTH levels. Non-PTH-mediated hypercalcemia can be due to malignancy, granulomatous disorders, pharmacologic agents, endocrinopathies, and genetic causes.

Hypocalcemia

Acute hypocalcemia (less than 8.5 mg/dL) can lead to syncope, congestive heart failure, numbness and tingling, muscle spasms and tetany, bronchospasm and wheezing, laryngospasm and dysphagia, irritability, depression, fatigue, and seizures. Chronic hypocalcemia can lead to coarse hair, brittle nails, psoriasis, dry skin, pruritus, poor dentition, and cataracts. The most common physical exam findings include neural hyperexcitability, psychological disturbances, and cardiac arrhythmias. The Chvostek and Trousseau signs are indicative of hypocalcemic states.

Sepsis and septic shock can cause hypocalcemia due to an unknown mechanism; patients with coexisting sepsis and hypocalcemia have higher mortality rates. A thorough medication history should be obtained to rule out hypocalcemia caused by medications such as cinacalcet, cisplatin, bisphosphonates, anticonvulsants, and denosumab.[8]

Diagnosis

The diagnosis of hypocalcemia is first achieved by measuring serum albumin, which distinguishes true hypocalcemia from factitious hypocalcemia due to hypoalbuminemia. If albumin is normal, PTH levels should be checked to determine if the hypocalcemia is due to a disorder of PTH such as hypoparathyroidism leading to rapid hypocalcemia known as a hungry bone syndrome. If PTH levels are normal, then magnesium, vitamin D, and phosphate levels can be checked to determine if calcium levels are being affected by other electrolyte abnormalities. It is always a good idea to check kidney and liver function to determine an end-organ cause of hypocalcemia. Equally, an electrocardiogram should be ordered to assess for the effect of hypocalcemia on the heart. Radiography is often indicated to determine the etiology of chronic hypocalcemia due to disorders such as rickets or osteomalacia.

Laboratory tests to determine the causes of hypercalcemia start with an albumin level and ionized calcium to confirm the hypercalcemia. Once confirmed, PTH levels should be checked to rule out hyperparathyroidism. Renal function and thyroid stimulating hormone (TSH) can hone in on nephrogenic and endocrine origins of hypercalcemia. Always consider electrolyte abnormalities in magnesium, vitamin D, and phosphate. An electrocardiogram may demonstrate a shortened QT interval, T wave flattening or inversion, J waves, or prolongation of the PR and QRS intervals.

The most common cause of rapidly progressive hypercalcemia is a malignancy, and patients should be evaluated radiographically for masses in the lung, breast, and kidney and have laboratory studies to evaluate for blood cancers such as multiple myeloma, lymphoma, and leukemia.

Treatment

The treatment of hypercalcemia or hypocalcemia focuses on correcting the underlying disorder, which is usually causing a disturbance in calcium homeostasis. In extreme circumstances, calcium supplementation or calciuresis can correct for severe derangements in calcium levels. For milder cases, supportive measures that enhance the function of the parathyroid glands, thyroid glands, kidneys, gut, and bone will allow the body to compensate for the excess or lack of calcium and utilize internal hormonal regulatory systems to bring the calcium levels back into homeostasis.

Dietary Use

A balanced diet includes 1000 mg of calcium daily. The intestine absorbs 200 to 400 mg of this with the rest excreted in the stool. Any excess calcium absorbed is secreted in urine. Calcium supplementation is common in elderly individuals, where it is prescribed with Vitamin D supplements to improve bone mass that is lost with increasing age.

Pharmacologic Use

The calcium salts of calcium chloride and calcium gluconate are administered in instances of severe hyperkalemia to stabilize the membrane potential and prevent prolonged cardiac muscle depolarization.[9][10]


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Physiology, Calcium - Questions

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What vitamin enhances the absorption of calcium?



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Where does calcium absorption normally take place?



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What is the normal level of calcium in the body?



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Parathyroid hormone needs the presence of vitamin D to promote absorption of calcium from which of the following sites?



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Where is calcium is absorbed?



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Which of the following vitamins enhances the absorption of calcium?



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A patient is taking calcium supplement to treat hypocalcemia. To facilitate absorption the patient should eat foods high in which of the following?



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A 25-year-old man is admitted to the trauma service after suffering severe burns to his chest, abdomen, and left arm after trying to put out a grease fire with water. In preparation for surgery, standard labs on the patient show calcium to be low at 7.0 mg/dL, and his albumin is 1.5 g/dL. What is the patient’s corrected calcium level?



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Physiology, Calcium - References

References

Effect of early overfeeding on palatable food preference and brain dopaminergic reward system at adulthood: role of calcium supplementation., Conceição EP,Carvalho JC,Manhães AC,Guarda DS,Figueiredo MS,Quitete FT,Oliveira E,Moura EG,Lisboa PC,, Journal of neuroendocrinology, 2016 Mar 1     [PubMed]
The Relationship of Physical Activity and Anthropometric and Physiological Characteristics to Bone Mineral Density in Postmenopausal Women., Arazi H,Eghbali E,Saeedi T,Moghadam R,, Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry, 2016 Feb 24     [PubMed]
The Role of Store-operated Calcium Channels in Pain., Munoz F,Hu H,, Advances in pharmacology (San Diego, Calif.), 2016     [PubMed]
Burgoyne RD,Helassa N,McCue HV,Haynes LP, Calcium Sensors in Neuronal Function and Dysfunction. Cold Spring Harbor perspectives in biology. 2019 Mar 4;     [PubMed]
Gerlinger C,Oster M,Borgelt L,Reyer H,Muráni E,Ponsuksili S,Polley C,Vollmar B,Reichel M,Wolf P,Wimmers K, Physiological and Transcriptional Responses in Weaned Piglets Fed Diets with Varying Phosphorus and Calcium Levels. Nutrients. 2019 Feb 20;     [PubMed]
Stewart TA,Davis FM, An element for development: Calcium signaling in mammalian reproduction and development. Biochimica et biophysica acta. Molecular cell research. 2019 Feb 28;     [PubMed]
Fukumoto S, [Osteocytes and Wnt signaling.] Clinical calcium. 2019;     [PubMed]
Keung L,Perwad F, Vitamin D and kidney disease. Bone reports. 2018 Dec;     [PubMed]
Rodríguez AJ,Scott D,Khan B,Hodge A,English DR,Giles GG,Abrahamsen B,Ebeling PR, High calcium intake in men not women is associated with all-cause mortality risk: Melbourne Collaborative Cohort Study. Archives of osteoporosis. 2018 Sep 21;     [PubMed]
Vassallo P,Green N,Courtney E, Hypercalcemia secondary to excessive self-medication with antacids causing acute pancreatitis: a case report. Croatian medical journal. 2019 Feb 28;     [PubMed]

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